Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial.

PURPOSE

To investigate safety, tolerability, dose-related pharmacologic properties, and pharmacodynamics of ZD1839 (gefinitib, Iressa; AstraZeneca Pharmacueticals, Wilmington, DE), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with solid tumor types known to express or highly express EGFR.

METHODS

This was an open-label, phase I, dose escalation safety/tolerability trial of oral ZD1839 (150 to 1,000 mg/d), administered once daily for 28-continuous-day cycles until disease progression or undue toxicity.

RESULTS

Of 71 (69 assessable for safety; 58 for efficacy) patients at seven dose levels, most had non-small-cell lung (n = 39) or head and neck (n = 18) cancer, and 68 of 71 patients received prior cancer therapy (two or more regimens in 54 patients [78%]). Diarrhea and rash, the primary dose-limiting toxicities (DLTs), occurred at 800 mg. Frequent treatment-related grade 1/2 adverse events were diarrhea (55%), asthenia (44%), and acne-like follicular rash (46%). At doses >or= 800 mg, 45% of patients required dose reductions. No increased or cumulative toxicity was observed over 250 patient-months of exposure. Pharmacokinetic analysis showed that steady-state occurred by day 7, interpatient exposure was more variable than intrapatient exposure, and variability of exposure did not change with dose. One patient experienced a partial response, but antitumor activity manifested mainly as prolonged stable disease (45% of patients >or= 3 months, 22% >or= 6 months, and 7.2% >or= 1 year). No relationship between dose, response, or duration on study was observed.

CONCLUSION

Rash and diarrhea, generally mild and tolerable at doses <or= 600 mg/d, were DLTs at 800 mg/d (maximum-tolerated dose). Antitumor activity was observed at all doses. Pharmacokinetic analyses confirmed suitability of once-daily oral dosing.